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Mutations in  PARK2 , encoding the E3 ubiquitin protein ligase Parkin, are a common cause of autosomal recessive Parkinson’s disease (PD). Loss of  PARK2  function compromises mitochondrial quality by affecting mitochondrial biogenesis, bioenergetics, dynamics, transport and turnover. We investigated the impact of  PARK2  dysfunction on the endoplasmic reticulum (ER)-mitochondria interface, which mediates calcium (Ca 2+ ) exchange between the two compartments and is essential for Parkin-dependent mitophagy. Confocal and electron microscopy analyses showed the ER and mitochondria to be in closer proximity in primary fibroblasts from  PARK2  knockout (KO) mice and PD patients with  PARK2  mutations than in controls. Ca 2+  flux to the cytosol was also modified, due to enhanced ER-to-mitochondria Ca 2+  transfers, a change that was also observed in neurons derived from induced pluripotent stem cells of a patient with  PARK2  mutations. Subcellular fractionation showed the abundance of the Parkin substrate mitofusin 2 (Mfn2), which is known to modulate the ER-mitochondria interface, to be specifically higher in the mitochondrion-associated ER membrane compartment in  PARK2  KO tissue. Mfn2 downregulation or the exogenous expression of normal Parkin restored cytosolic Ca 2+  transients in fibroblasts from patients with  PARK2  mutations. In contrast, a catalytically inactive PD-related Parkin variant had no effect. Overall, our data suggest that Parkin is directly involved in regulating ER-mitochondria contacts and provide new insight into the role of the loss of Parkin function in PD development.

The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations